The indole derivative NecroX‐7 improves nonalcoholic steatohepatitis in ob/ob mice through suppression of mitochondrial ROS/RNS and inflammation. (10th January 2015)

• Record Type: Journal Article
• Authors: Chung, Hyo Kyun; Kim, Yong Kyung; Park, Ji‐Hoon; Ryu, Min Jeong; Chang, Joon Young; Hwang, Jung Hwan; Lee, Chul‐Ho; Kim, Soon‐Ha; Kim, Hyun Jin; Kweon, Gi Ryang; Kim, Koon Soon; Shong, Minho
• Is Part Of: Liver international. Volume 35:Number 4(2015:Apr.)
• Page Start: 1341
• Page End: 1353
• Publication Date: 2015-01-10
• Subjects: Liver -- Periodicals; Liver -- Diseases -- Periodicals; 616.362
• DOI: 10.1111/liv.12741
• Languages: English
• ISSNs: 1478-3223

Abstract

<abstract abstract-type="main" id="liv12741-abs-0001"> <title>Abstract</title> <sec id="liv12741-sec-0001" sec-type="section"> <title>Background & Aims</title> <p>Nonalcoholic steatohepatitis (NASH) is associated with cirrhosis and hepatocellular carcinoma. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play key roles in the development of the disease. However, the therapeutic target of NASH has not been fully defined and new treatments are needed. We investigated the protective effects of the antioxidant indole‐derived NecroX‐7 in a NASH mouse model using leptin‐deficient <italic>ob/ob</italic> and methionine‐ and choline‐deficient (MCD) diet‐fed <italic>ob/ob</italic> mice.</p> </sec> <sec id="liv12741-sec-0002" sec-type="section"> <title>Methods</title> <p>Six‐week‐old male mice were divided into three groups: <italic>ob/+</italic> mice, <italic>ob/ob</italic> mice treated with vehicle and <italic>ob/ob</italic> mice treated daily with NecroX‐7 (20 mg/kg) for 4 weeks. To study the effects of NecroX‐7 in a fibrosis model, NASH was induced by feeding <italic>ob/ob</italic> mice an MCD diet. The effects of NecroX‐7 on NASH progression were evaluated using biochemical, histological and molecular markers.</p> </sec> <sec id="liv12741-sec-0003" sec-type="section"> <title>Results</title> <p>NecroX‐7‐treated <italic>ob/ob</italic> mice had a marked decrease in serum aspartate aminotransferase and alanine transaminase compared with vehicle‐treated controls. Interestingly, hepatic steatosis and lipid peroxidation were significantly improved by NecroX‐7 treatment. NecroX‐7 inhibited <italic>tert</italic>‐butylhydroperoxide‐ and H<sub>2</sub>O<sub>2</sub>‐induced mitochondrial ROS/RNS in primary hepatocytes and attenuated mitochondrial dysfunction <italic>in vitro</italic> and <italic>in vivo</italic>. Furthermore, NecroX‐7‐treated mice exhibited fewer infiltrating macrophages and reduced hepatic tumour necrosis factor‐alpha expression. Hepatic fibrosis in MCD‐fed <italic>ob/ob</italic> mice was significantly decreased by NecroX‐7 treatment.</p> </sec> <sec id="liv12741-sec-0004" sec-type="section"> <title>Conclusions</title> <p>NecroX‐7 treatment improved hepatic steatosis and fibrosis in murine NASH models. These effects occurred through the suppression of whole‐cell ROS/RNS and inflammatory responses and suggest that NecroX‐7 has a potential therapeutic benefit in steatohepatitis.</p> </sec> </abstract>